Coatings containing multiple drugs

ABSTRACT

A method for depositing a coating comprising a polymer and at least two pharmaceutical agents on a substrate, comprising the following steps: providing a stent framework; depositing on said stent framework a first layer comprising a first pharmaceutical agent; depositing a second layer comprising a second pharmaceutical agent; Wherein said first and second pharmaceutical agents are selected from two different classes of pharmaceutical agents.

CROSS-REFERENCE

This application is a continuation of U.S. application Ser. No.12/298,459, filed Mar. 16, 2009, which was filed pursuant to 35 U.S.C.§371 as a U.S. National Phase Application of International ApplicationNo. PCT/US2007/010227, filed Apr. 26, 2007, which claims the benefit ofU.S. Provisional Application Nos. 60/912,394 filed Apr. 17, 2007;60/745,731 filed Apr. 26, 2006; and 60/745,733 filed Apr. 26, 2006, eachof which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

The present invention relates to methods for depositing a coatingcomprising a polymer and a pharmaceutical or biological agent in powderform onto a substrate.

It is often beneficial to provide coatings onto substrates, such thatthe surfaces of such substrates have desired properties or effects.

For example, it is useful to coat biomedical implants to provide for thelocalized delivery of pharmaceutical or biological agents to targetspecific locations within the body, for therapeutic or prophylacticbenefit. One area of particular interest is that of drug eluting stents(DES) that has recently been reviewed by Ong and Serruys in Nat. Clin.Pract. Cardiovasc. Med., (December 2005), Vol 2, No 12, 647. Typicallysuch pharmaceutical or biological agents are co-deposited with apolymer. Such localized delivery of these agents avoids the problems ofsystemic administration, which may be accompanied by unwanted effects onother parts of the body, or because administration to the afflicted bodypart requires a high concentration of pharmaceutical or biological agentthat may not be achievable by systemic administration. The coating mayprovide for controlled release, including long-term or sustainedrelease, of a pharmaceutical or biological agent. Additionally,biomedical implants may be coated with materials to provide beneficialsurface properties, such as enhanced biocompatibility or lubriciousness.

Conventionally, coatings have been applied by processes such as dipping,spraying, vapor deposition, plasma polymerization, andelectro-deposition. Although these processes have been used to producesatisfactory coatings, there are drawbacks associated therewith. Forexample it is often difficult to achieve coatings of uniform thicknessesand prevent the occurrence of defects (e.g. bare spots). Also, in manyprocesses, multiple coating steps are frequently necessary, usuallyrequiring drying between or after the coating steps.

Another disadvantage of most conventional methods is that manypharmaceutical or biological agents, once deposited onto a substrate,suffer from poor bioavailability, reduced shelf life, low in vivostability or uncontrollable elution rates, often attributable to poorcontrol of the morphology and/or secondary structure of the agent.Pharmaceutical agents present significant morphology control challengesusing existing spray coating techniques, which conventionally involve asolution containing the pharmaceutical agents being spayed onto asubstrate. As the solvent evaporates the agents are typically left in anamorphous state. Lack of or low degree of crystallinity of the spraycoated agent can lead to decreased shelf life and too rapid drugelution. Biological agents typically rely, at least in part, on theirsecondary, tertiary and/or quaternary structures for their activity.While the use of conventional solvent-based spray coating techniques maysuccessfully result in the deposition of a biological agent upon asubstrate, it will often result in the loss of at least some of thesecondary, tertiary and/or quaternary structure of the agent andtherefore a corresponding loss in activity. For example, many proteinslose activity when formulated in carrier matrices as a result of theprocessing methods.

Conventional solvent-based spray coating processes are also hampered byinefficiencies related to collection of the coating constituents ontothe substrate and the consistency of the final coating. As the size ofthe substrate decreases, and as the mechanical complexity increases, itgrows increasingly difficult to uniformly coat all surfaces of asubstrate.

What is needed is a cost-effective method for depositing inert polymersand pharmaceutical or biological agents onto a substrate, where thecollection process is efficient, the coating produced is conformal,substantially defect-free and uniform, the composition of the coatingcan be regulated and the morphology and/or secondary structure of thepharmaceutical or biological agents can be controlled. The method wouldthus permit structural and morphological preservation of the agentsdeposited during the coating process.

SUMMARY OF THE INVENTION

A first aspect of the invention provides methods for depositing acoating comprising a polymer and pharmaceutical agent on a substrate,comprising discharging at least one pharmaceutical agent in atherapeutically desirable morphology in dry powder form through a firstorifice; discharging at least one polymer in dry powder form through asecond orifice; depositing the polymer and/or pharmaceutical particlesonto said substrate, wherein an electrical potential is maintainedbetween the substrate and the pharmaceutical and/or polymer particles,thereby forming said coating; and sintering said coating underconditions that do not substantially modify the morphology of saidpharmaceutical agent.

Although the size, resistivity and moisture content of the polymer andpharmaceutical agent may vary widely based on the conditions used,desired particle sizes are typically in the range of 0.01 μm-2500 μm,and more preferably in the range of 0.01 μm-100 μm, resistivity istypically in the range of from about 106 Ωm to about 1024 Ωm andmoisture content is less than 5% by weight. In one embodiment of theinvention the molecular weight range of the polymer is from about 5,000a.u. to about 100,000 a.u. In other embodiments, the first and secondorifices are provided as one single orifice wherein the pharmaceuticalagent and polymer may be mixed together prior to discharging. In yetother embodiments the pharmaceutical agent and polymer particles may bedischarged simultaneously or in succession. In another embodiment of theinvention the method further comprises discharging a third dry powdercomprising a second pharmaceutical agent whereby a coating comprising atleast two different pharmaceutical agents is deposited on saidsubstrate. In some embodiments, the therapeutically desirable morphologyof said pharmaceutical agent is crystalline or semi-crystalline, whereinpreferably at least 50% of said pharmaceutical agent in powder form iscrystalline or semicrystalline. In certain other embodiments of theinvention the pharmaceutical agent is prepared by milling, jet-milling,granulation, spray drying, crystallizing or fluidizing and in apreferred embodiment the therapeutically desirable morphology is notsubstantially changed after the step of sintering the coating. In afurther embodiment the pharmaceutical agent and/or the polymer becomeselectrostatically charged prior to deposition, and the substrate may beelectrically grounded. In a preferred embodiment, the substrate iselectrostatically charged. In some embodiments the polymer andpharmaceutical agent are discharged using a gas based propellant, whichtypically comprises carbon dioxide, nitrous oxide, hydrofluorocarbons,chlorofluorocarbons, helium, nitrogen, compressed air, argon, orvolatile hydrocarbons with a vapor pressure greater than 750 Torr at 20°C., and is preferably carbon dioxide. In one embodiment of the inventionthe pharmaceutical agent comprises at least one drug, which may beselected from Sirolimus, Tacrolimus, Everolimus, Zotarolimus, and Taxol.In another embodiment of the invention the ratio of pharmaceutical agentto polymer is from about 1:50 to about 5:1. In some embodiments, theamount of pharmaceutical agent will depend on the particular agent beingemployed, the type of substrate, and the medical condition beingtreated. Typically, the amount of pharmaceutical agent is about 0.001percent to about 70 percent, more typically about 0.001 percent to about50 percent, most typically about 0.001 percent to about 20 percent byweight of the polymer/pharmaceutical agent combination. In otherembodiments, however, the present invention permits “high load”formulation where the coating composition comprises at least 50, 60, 70or 80 percent by weight of the pharmaceutical agent, combined with notmore than 50, 40, 30 or 20 percent by weight of polymer composition.

Another aspect of the invention provides methods for depositing acoating comprising an active biological agent and a polymer on asubstrate, comprising discharging at least one active biological agentthrough a first orifice; discharging at least one polymer in dry powderform through a second orifice; depositing the active biological agentand/or polymer particles onto said substrate, wherein an electricalpotential is maintained between the substrate and the active biologicalagent and/or polymer particles, thereby forming said coating; andsintering said coating under conditions that do not substantially modifythe activity of said biological agent.

In some embodiments the activity of the active biological agent is oftherapeutic or prophylactic value and may be influenced by itssecondary, tertiary or quaternary structure. In a preferred embodimentof the invention, the active biological agent possesses a secondary,tertiary or quaternary structure which is not substantially changedafter sintering. In one embodiment of the invention the activebiological agent is a peptide, protein, enzyme, nucleic acid, antisensenucleic acid, antimicrobial, vitamin, hormone, steroid, lipid,polysaccharide or carbohydrate, and may further comprise a stabilizingagent. Most preferably the active biological agent is a peptide, proteinor enzyme. In other embodiments, the active biological agent is providedas a dry powder Although the size, resistivity and moisture content ofthe active biological agent and polymer may vary widely based on theconditions used, desired particle sizes are typically in the range of0.01 μm-2500 μm, and more preferably in the range of 0.01 μm-100 μm,resistivity is typically in the range of from about 106 Ωm to about 1024Ωm and moisture content is less than 5% by weight. In one embodiment ofthe invention the molecular weight range of the polymer is from about5,000 a.u. to about 100,000 a.u. In other embodiments, the first andsecond orifices are provided as one single orifice wherein thepharmaceutical agent and polymer may be mixed together prior todischarging. In yet other embodiments the pharmaceutical agent andpolymer particles may be discharged simultaneously or in succession. Inanother embodiment of the invention the method further comprisesdischarging a second active biological agent whereby a coatingcomprising at least two different biological agents is deposited on saidsubstrate. In a further embodiment the biological agent and/or thepolymer becomes electrostatically charged prior to deposition, and thesubstrate may be electrically grounded. In a preferred embodiment, thesubstrate is electrostatically charged. In some embodiments the polymerand biological agent are discharged using a gas based propellant, whichtypically, comprises carbon dioxide, nitrous oxide, hydrofluorocarbons,chlorofluorocarbons, helium, nitrogen, compressed air or volatilehydrocarbons with a vapor pressure greater than 750 Torr at 20° C., andis preferably carbon dioxide. In another embodiment of the invention theratio of biological agent to polymer is from about 1:50 to about 5:1. Insome embodiments, the amount of biological agent will depend on theparticular agent being employed, the type of substrate, and the medicalcondition being treated. Typically, the amount of biological agent isabout 0.001 percent to about 70 percent, more typically about 0.001percent to about 50 percent, most typically about 0.001 percent to about20 percent by weight of the polymer/biological agent combination. Inother embodiments, however, the present invention permits “high load”formulation where the coating composition comprises at least 50, 60, 70or 80 percent by weight of the biological agent, combined with not morethan 50, 40, 30 or 20 percent by weight of polymer composition.

Yet another aspect of the invention provides methods for depositing acoating comprising a polymer and a pharmaceutical agent on a substrate,comprising discharging at least one pharmaceutical agent in atherapeutically desirable morphology in dry powder form through a firstorifice; forming a supercritical or near supercritical fluid mixturethat includes at least one supercritical fluid solvent and at least onepolymer and discharging said supercritical or near supercritical fluidsolution through a second orifice under conditions sufficient to formsolid particles of the polymer; depositing the polymer and/orpharmaceutical particles onto said substrate, wherein an electricalpotential is maintained between the substrate and the pharmaceuticaland/or polymer particles, thereby forming said coating and sinteringsaid coating under conditions that do not substantially modify themorphology of said solid pharmaceutical particles.

Although the size, resistivity and moisture content of thepharmaceutical agent may vary widely based on the conditions used,desired particle sizes are typically in the range of 0.01 μm-2500 μm,and more preferably in the range of 0.01 μm-100 μm, resistivity istypically in the range of from about 106 Ωm to about 1024 Ωm andmoisture content is less than 5% by weight. In one embodiment of theinvention, the molecular weight range of the polymer is from about 5,000a.u. to about 100,000 a.u. In one embodiment of the invention thepharmaceutical and polymer particles are discharged simultaneously,while in another embodiment of the invention they are discharged insuccession. In another embodiment of the invention the method furthercomprises discharging a second dry powder comprising a secondpharmaceutical agent whereby a coating comprising at least two differentpharmaceutical agents is deposited on said substrate. In someembodiments, the therapeutically desirable morphology of saidpharmaceutical agent is crystalline or semi-crystalline, whereinpreferably at least 50% of said pharmaceutical agent in powder form iscrystalline or semicrystalline. In certain other embodiments of theinvention the pharmaceutical agent is prepared by milling, jet-milling,granulation, spray drying, crystallizing or fluidizing and in apreferred embodiment the therapeutically desirable morphology is notsubstantially changed after the step of sintering the coating. In afurther embodiment the pharmaceutical agent and/or the polymer becomeselectrostatically charged prior to deposition, and the substrate may beelectrically grounded. In a preferred embodiment, the substrate iselectrostatically charged. In some embodiments the pharmaceutical agentis discharged using a gas based propellant, which typically comprisescarbon dioxide, nitrous oxide, hydrofluorocarbons, chlorofluorocarbons,helium, nitrogen, compressed air or volatile hydrocarbons with a vaporpressure greater than 750 Torr at 20° C., and is preferably carbondioxide. In one embodiment of the invention the pharmaceutical agentcomprises at least one drug, which may be selected from [list]. Inanother embodiment of the invention the ratio of pharmaceutical agent topolymer is from about 1:50 to about 5:1. In some embodiments, the amountof pharmaceutical agent will depend on the particular agent beingemployed, the type of substrate, and the medical condition beingtreated. Typically, the amount of pharmaceutical agent is about 0.001percent to about 70 percent, more typically about 0.001 percent to about50 percent, most typically about 0.001 percent to about 20 percent byweight of the polymer/pharmaceutical agent combination. In otherembodiments, however, the present invention permits “high load”formulation where the coating composition comprises at least 50, 60, 70or 80 percent by weight of the pharmaceutical agent, combined with notmore than 50, 40, 30 or 20 percent by weight of polymer composition.

A further aspect of the invention provides methods for depositing acoating comprising an active biological agent and a polymer on asubstrate, comprising discharging at least one active biological agentthrough a first orifice; forming a supercritical or near supercriticalfluid mixture that includes at least one supercritical fluid solvent andat least one polymer and discharging said supercritical or nearsupercritical fluid solution through a second orifice under conditionssufficient to form solid particles of the polymer; depositing the activebiological agent and/or polymer particles onto said substrate, whereinan electrical potential is maintained between the substrate and theactive biological agent and/or polymer particles, thereby forming saidcoating and sintering said coating under conditions that do notsubstantially modify the activity of said biological agent.

In some embodiments the activity of the active biological agent is oftherapeutic or prophylactic value and may be influenced by itssecondary, tertiary or quaternary structure. In a preferred embodimentof the invention, the active biological agent possesses a secondary,tertiary or quaternary structure which is not substantially changedafter sintering. In one embodiment of the invention the activebiological agent is a peptide, protein, enzyme, nucleic acid, antisensenucleic acid, antimicrobial, vitamin, hormone, steroid, lipid,polysaccharide or carbohydrate, and may further comprise a stabilizingagent. Most preferably the active biological agent is a peptide, proteinor enzyme. In other embodiments, the active biological agent is providedas a dry powder. Although the size, resistivity and moisture content ofthe active biological agent may vary widely based on the conditionsused, desired particle sizes are typically in the range of 0.01 μm-2500μm, and more preferably in the range of 0.01 μm-100 μm, resistivity istypically in the range of from about 106 Ωm to about 1024 Ωm andmoisture content is less than 5% by weight. In one embodiment of theinvention the molecular weight range of the polymer is from about 5,000a.u. to about 100,000 a.u. In one embodiment of the invention thebiological agent and polymer particles are discharged simultaneously,while in another embodiment of the invention they are discharged insuccession. In another embodiment of the invention the method furthercomprises discharging second active biological agent whereby a coatingcomprising at least two different biological agents is deposited on saidsubstrate. In a further embodiment the biological agent and/or thepolymer becomes electrostatically charged prior to deposition, and thesubstrate may be electrically grounded. In a preferred embodiment, thesubstrate is electrostatically charged. In some embodiments thebiological agent is discharged using a gas based propellant, whichtypically comprises carbon dioxide, nitrous oxide, hydrofluorocarbons,chlorofluorocarbons, helium, nitrogen, compressed air or volatilehydrocarbons with a vapor pressure greater than 750 Torr at 20° C., andis preferably carbon dioxide. In another embodiment of the invention theratio of biological agent to polymer is from about 1:50 to about 5:1. Insome embodiments, the amount of biological agent will depend on theparticular agent being employed, the type of substrate, and the medicalcondition being treated. Typically, the amount of biological agent isabout 0.001 percent to about 70 percent, more typically about 0.001percent to about 50 percent, most typically about 0.001 percent to about20 percent by weight of the polymer/biological agent combination. Inother embodiments, however, the present invention permits “high load”formulation where the coating composition comprises at least 50, 60, 70or 80 percent by weight of the biological agent, combined with not morethan 50, 40, 30 or 20 percent by weight of polymer composition.

Each of the above methods may be carried out from about 0° C. to about80° C. and from about 0.1 atmospheres to about 73 atmospheres, in eitheropen or closed vessel. In some embodiments, the substrate is abiomedical implant which may be a stent, electrode, catheter, lead,implantable pacemaker or cardioverter housing, joint, screw, rod,ophthalmic implant, prosthetic or shunt.

In some embodiments of the invention the thickness of said coating isfrom about 1 to about 100 μm, preferably about 10 μm, and the variationin the thickness along said coating is within 0.5 μm, within 0.25 μm,within 0.1 μm or within 10% of the total thickness of said coating,within 5% of the total thickness of said coating, or within 2.5% of thetotal thickness of said coating. In other embodiments, the XRD patternof said pharmaceutical agent or active biological agent comprises atleast two, at least five and preferably at least ten of the same peaksafter the coating process, as compared to the XRD pattern of saidpharmaceutical agent or active biological agent prior to the coatingprocess. In yet other embodiments, the pharmaceutical agent or activebiological agent is positioned at a selected distance from top of saidcoating. In further embodiments, the pharmaceutical agent or activebiological agent is positioned at about midway between the top of saidcoating and the substrate surface. In other embodiments of the inventionthe variability in the amount of pharmaceutical agent or activebiological agent deposited on said substrate is 20% or less, 15% orless, 10% or less, 5% or less, for a batch of substrates coated at thesame time. Preferably the variability is 5% or less. In yet otherembodiments of the invention, the methods further comprise depositing atop layer on said coating wherein said top layer is a polymer film. Insome embodiments, the polymer film has a thickness of 0.5 to 10 microns,and can be deposited by a RESS or SEDS process. In yet otherembodiments, the polymer film is formed by depositing a single polymerand can be formed by depositing substantially pure PBMA.

The invention further relates to the use of a supercritical solutioncomprising a second fluid in its supercritical state.

In some embodiments, the addition of a second fluid in its supercriticalstate is to act as a flammability suppressor. In other embodiments, asecond fluid is used, wherein said second fluid has critical parameterslower than the first fluid's critical parameters, and therefore lowersthe critical properties of the mixture/solution enabling access to themixture supercritical state.

In some embodiments the supercritical solution comprises isobutylene. Inother embodiments, the supercritical fluid comprises isobutylene andcarbon dioxide as a second fluid.

Other embodiments of the invention provide a way to dissolve twopolymers in a supercritical solvent. In some embodiments said twopolymers are PEVA and PBMA. In other embodiments, a supercriticalsolution comprising two polymers is used to create a RESS spray of thepolymers generating ˜10 to 100 nm particles of each polymer. In furtherembodiments, PEVA and PBMA are dissolved in a supercritical solvent thatfurther comprises CO2 to act as a fire suppressor in the event of anignition source causing a fire.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1. Schematic Representation of the Coating and Sintering ProcessApparatus, as discussed in example 9.

FIG. 2. Detailed images of the Coating and Sintering Process Apparatus,as discussed in example 9.

FIG. 3. Drug-Polymer coated coronary stent (a) immediately afterdeposition, (b) after annealing in a dense carbon dioxide environment at40° C.; the photographs correspond to the experiment discussed inconjunction with Example 10.

FIG. 4. 40× Magnified Images of Rapamycin/PEVA/PBMA Coated Stents,Obtained From an Optical Microscope with Back and Side Lighting, Showingthe Outside, Edge and Inside Surfaces, (a) before and (b) aftersintering, as discussed in example 10.

FIG. 5. 40× Magnified Images of Rapamycin/PEVA/PBMA Coated Stents,Obtained From an Optical Microscope with Back and Side Lighting, Showingthe Outside and Inside Surfaces, (a) before and (b) after sintering, asdiscussed in example 10.

FIG. 6. 100× Magnified Image of a Rapamycin/PEVA/PBMA Coated Stent,Obtained From an Optical Microscope. Crystalline drug is clearly visibleembedded within a highly uniform polymer coating, as discussed inexample 10.

FIG. 7. Scanning Electron Microscope Images of Rapamycin/PEVA/PBMACoated Stents, at (a) ×30 magnification, (b) ×250 magnification, (c)×1000 magnification and (d) ×3000 magnification, as discussed in example11.

FIG. 8. Cross-sectional Scanning Electron Microscope Images ofRapamycin/PEVA/PBMA Coated Stents at (a) ×7000 magnification and (b)×20000 magnification. Four cross-sectional thicknesses measured: (1)10.355 μM; (2) 10.412 μM; (3) 10.043 μM and (4) 10.157 μM, providing acalculated average thickness of 10.242 μM±2%, also discussed in example11.

FIG. 9. Differential Scanning calorimetry (DSC) of (a) PEVA Control, (b)PBMA Control, (c) Rapamycin Control and (d) Coated Rapamycin, PEVA, PBMAMixture. The Rapamycin crystalline melt at 185-200° C. is indicated in(c) and (d), as discussed in example 12.

FIG. 10. X-Ray Diffraction of (a) Microionized Rapamycin Powder(Control) and (b) Coated Sintered Rapamycin/PEVA/PBMA Stents, asdiscussed in example 13.

FIG. 11. Confocal Raman Analysis of Rapamycin/PEVA/PBMA Coated Stents(i.e. Depth Profiling from Coating Surface to Metal Stent), highlighting(a) Rapamycin Depth Profile Outside Circumference and (b) Polymer DepthProfile Outside Circumference, as discussed in example 14.

FIG. 12. (a) Rapamycin UV-Vis Spectrum and (b) Calibration Curve at 277nm, (c) PEVA/PBMA FT-IR Spectrum, (d) PEVA Calibration Curve at 1050 nmand (e) PBMA Calibration Curve at 1285 nm.

FIG. 13. Quantification of Coating Components, (mean concentrations (3stents each); 4 cell by 8 mm parylene coated). (a) RapamycinQuantification (74±11 μg) Using UV-Vis Method; (b) PEVA (1060±190 μg)and (c) PBMA (1110±198 μg) Quantification Using FT-IR Method, asdiscussed in example 15.

FIG. 14. Optical Microscopy Showing the Outside Surface of a 3 mmGuidant TriStar® Stent Coated with Paclitaxel-polymer composite, asdiscussed in example 16.

FIG. 15. Paclitaxel Quantification After Coating on a 3 mm GuidantTriStar® Stent with Paclitaxel/PEVA/PMBA composite, as discussed inexample 16. (a) Calibration Curve at 228 nm in ethanol Using UV-VisStandard Method and (b) Quantification (148±14 μg) Using UV-Vis Method

FIG. 16. Quantification of Coating Components, (mean concentrations (3stents each); 6 cell by 8 mm parylene coated). (a) RapamycinQuantification (81±3 μg) Using UV-Vis Method; (b) PEVA (391±69 μg) and(c) PBMA (268±64 μg) Quantification Using FT-IR Method, as discussed inexample 17.

FIG. 17. Cloud point isotherms for polyethylene-co-vinyl acetate (PEVA)and poly(butyl methacrylate) (PMBA) combined as discussed in examples19, 20, 21 and 22.

FIGS. 18-24 illustrate particular embodiments of the invention

DETAILED DESCRIPTION OF THE INVENTION

The present invention is explained in greater detail below. Thisdescription is not intended to be a detailed catalog of all thedifferent ways in which the invention may be implemented, or all thefeatures that may be added to the instant invention. For example,features illustrated with respect to one embodiment may be incorporatedinto other embodiments, and features illustrated with respect to aparticular embodiment may be deleted from that embodiment. In addition,numerous variations and additions to the various embodiments suggestedherein will be apparent to those skilled in the art in light of theinstant disclosure, which do not depart from the instant invention.Hence, the following specification is intended to illustrate someparticular embodiments of the invention, and not to exhaustively specifyall permutations, combinations and variations thereof.

Applicants specifically intend that all United States patent referencescited herein be incorporated herein by reference in their entirety.

The present invention provides a cost-effective, efficient method fordepositing a combination of an inert polymer or polymers and apharmaceutical or biological agent or agents, onto parts or all surfacesof a substrate, to form a coating that is of a pre-determined, desiredthickness, conformal, substantially defect-free, and uniform and thecomposition of the coating can be regulated. In particular, the presentinvention addresses the problem of existing coating processes, which donot allow for structural and morphological preservation of the agentsdeposited during the coating process.

The first aspect of the invention entails the deposition of thepharmaceutical or biological agents as dry powders, using electrostaticcapture to attract the powder particles to the substrate. Dry powderspraying is well known in the art, and dry powder spraying coupled withelectrostatic capture has been described, for example in U.S. Pat. Nos.5,470,603 6,319,541 or 6,372,246. The deposition of the polymer can beperformed in any number of standard procedures, as the morphology of thepolymer, so long as it provides coatings possessing the desiredproperties (e.g. thickness, conformity, defect-free, uniformity etc), isof less importance. The function of the polymer is primarily one ofinert carrier matrix for the active components of the coating.

The second step of the coating process involves taking the substratesthat have been coated with pharmaceutical or biological agents andpolymers and subjecting them to a sintering process that takes placeunder benign conditions, which do not affect the structural andmorphological integrity of the pharmaceutical and biological agents. Thesintering process as used in the current invention refers to the processby which the co-deposited pharmaceutical agent or biologicalagent-polymer matrix, becomes fused and adherent to the substrate bytreatment of the coated substrate with a compressed gas, compressedliquid, or supercritical fluid that is a non-solvent for the polymers,the pharmaceutical agents and the biological agents, but a plasticizingagent for the polymer. The sintering process takes place underconditions (e.g. mild temperatures), and using benign fluids (e.g.supercritical carbon dioxide) which will not affect the structural andmorphological integrity of the pharmaceutical and biological agents.

One aspect of the invention is the combination of two or more of the drypowder, RESS and SEDS spraying techniques. In all aspects of theinvention a pharmaceutical or biological agent is deposited onto asubstrate by dry powder spraying.

A specific aspect of the invention involves the dry powder spraying of apharmaceutical agent, in a preferred particle size and morphology, intothe same capture vessel as a polymer that is also dry powder sprayed,whereby the spraying of the agent and the polymer is sequential orsimultaneous.

Another specific aspect of the invention involves the dry powderspraying of an active biological agent, in a preferred particle size andpossessing a particular activity, into the same capture vessel as apolymer that is also dry powder sprayed, whereby the spraying of theagent and the polymer is sequential or simultaneous.

Yet another aspect of the invention involves the dry powder spraying ofa pharmaceutical agent, in a preferred particle size and morphology,into the same capture vessel as a polymer that is sequentially orsimultaneously sprayed by the RESS spray process.

Yet another aspect of the invention involves the dry powder spraying ofan active biological agent, in a preferred particle size and possessinga particular activity, into the same capture vessel as a polymer that issequentially or simultaneously sprayed by the RESS spray process.

Yet another aspect of the invention involves the dry powder spraying ofa pharmaceutical agent, in a preferred particle size and morphology,into the same capture vessel as a polymer that is sequentially orsimultaneously sprayed by the SEDS spray process.

Yet another aspect of the invention involves the dry powder spraying ofan active biological agent, in a preferred particle size and possessinga particular activity, into the same capture vessel as a polymer that issequentially or simultaneously sprayed by the SEDS spray process.

Any combination of the above six processes is contemplated by thisaspect of the invention.

In further aspects of the invention the substrates that have been coatedwith pharmaceutical or biological agents and polymers, as described inthe above embodiments are then subjected to a sintering process. Thesintering process takes place under benign conditions, which do notaffect the structural and morphological integrity of the pharmaceuticaland biological agents, and refers to a process by which the co-depositedpharmaceutical agent or biological agent-polymer matrix, becomes fusedand adherent to the substrate. This is achieved by treating the coatedsubstrate with a compressed gas, compressed liquid or supercriticalfluid that is a non-solvent for the polymers, the pharmaceutical agentsand the biological agents, but a plasticizing agent for the polymer. Thesintering process takes place under conditions (e.g. mild temperatures),and using benign fluids (e.g. supercritical carbon dioxide) which willnot affect the structural and morphological integrity of thepharmaceutical and biological agents. Other sintering processes, whichdo not affect the structural and morphological integrity of thepharmaceutical and biological agents may also be contemplated by thepresent invention.

Definitions

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

“Substrate” as used herein, refers to any surface upon which it isdesirable to deposit a coating comprising a polymer and a pharmaceuticalor biological agent, wherein the coating process does not substantiallymodify the morphology of the pharmaceutical agent or the activity of thebiological agent. Biomedical implants are of particular interest for thepresent invention; however the present invention is not intended to berestricted to this class of substrates. Those of skill in the art willappreciate alternate substrates that could benefit from the coatingprocess described herein, such as pharmaceutical tablet cores, as partof an assay apparatus or as components in a diagnostic kit (e.g. a teststrip).

“Biomedical implant” as used herein refers to any implant for insertioninto the body of a human or animal subject, including but not limited tostents (e.g., vascular stents), electrodes, catheters, leads,implantable pacemaker, cardioverter or defibrillator housings, joints,screws, rods, ophthalmic implants, femoral pins, bone plates, grafts,anastomotic devices, perivascular wraps, sutures, staples, shunts forhydrocephalus, dialysis grafts, colostomy bag attachment devices, eardrainage tubes, leads for pace makers and implantable cardioverters anddefibrillators, vertebral disks, bone pins, suture anchors, hemostaticbarriers, clamps, screws, plates, clips, vascular implants, tissueadhesives and sealants, tissue scaffolds, various types of dressings(e.g., wound dressings), bone substitutes, intraluminal devices,vascular supports, etc.

The implants may be formed from any suitable material, including but notlimited to organic polymers (including stable or inert polymers andbiodegradable polymers), metals, inorganic materials such as silicon,and composites thereof, including layered structures with a core of onematerial and one or more coatings of a different material. However, theinvention contemplates the use of electrostatic capture in conjunctionwith substrate having low conductivity or which non-conductive. Toenhance electrostatic capture when a non-conductive substrate isemployed, the substrate is processed while maintaining a strongelectrical field in the vicinity of the substrate.

Subjects into which biomedical implants of the invention may be appliedor inserted include both human subjects (including male and femalesubjects and infant, juvenile, adolescent, adult and geriatric subjects)as well as animal subjects (including but not limited to dog, cat,horse, monkey, etc.) for veterinary purposes.

In a preferred embodiment the biomedical implant is an expandableintraluminal vascular graft or stent (e.g., comprising a wire mesh tube)that can be expanded within a blood vessel by an angioplasty balloonassociated with a catheter to dilate and expand the lumen of a bloodvessel, such as described in U.S. Pat. No. 4,733,665 to Palmaz.

“Pharmaceutical agent” as used herein refers to any of a variety ofdrugs or pharmaceutical compounds that can be used as active agents toprevent or treat a disease (meaning any treatment of a disease in amammal, including preventing the disease, i.e. causing the clinicalsymptoms of the disease not to develop; inhibiting the disease, i.e.arresting the development of clinical symptoms; and/or relieving thedisease, i.e. causing the regression of clinical symptoms). It ispossible that the pharmaceutical agents of the invention may alsocomprise two or more drugs or pharmaceutical compounds. Pharmaceuticalagents, include but are not limited to antirestenotic agents,antidiabetics, analgesics, antiinflammatory agents, antirheumatics,antihypotensive agents, antihypertensive agents, psychoactive drugs,tranquillizers, antiemetics, muscle relaxants, glucocorticoids, agentsfor treating ulcerative colitis or Crohn's disease, antiallergics,antibiotics, antiepileptics, anticoagulants, antimycotics, antitussives,arteriosclerosis remedies, diuretics, proteins, peptides, enzymes,enzyme inhibitors, gout remedies, hormones and inhibitors thereof,cardiac glycosides, immunotherapeutic agents and cytokines, laxatives,lipid-lowering agents, migraine remedies, mineral products, otologicals,anti parkinson agents, thyroid therapeutic agents, spasmolytics,platelet aggregation inhibitors, vitamins, cytostatics and metastasisinhibitors, phytopharmaceuticals, chemotherapeutic agents and aminoacids. Examples of suitable active ingredients are acarbose, antigens,beta-receptor blockers, non-steroidal antiinflammatory drugs [NSAIDs],cardiac glycosides, acetylsalicylic acid, virustatics, aclarubicin,acyclovir, cisplatin, actinomycin, alpha- and beta-sympatomimetics,(omeprazole, allopurinol, alprostadil, prostaglandins, amantadine,ambroxol, amlodipine, methotrexate, S-aminosalicylic acid [sic],amitriptyline, amoxicillin, anastrozole, atenolol, azathioprine,balsalazide, beclomethasone, betahistine, bezafibrate, bicalutamide,diazepam and diazepam derivatives, budesonide, bufexamac, buprenorphine,methadone, calcium salts, potassium salts, magnesium salts, candesartan,carbamazepine, captopril, cefalosporins, cetirizine, chenodeoxycholicacid, ursodeoxycholic acid, theophylline and theophylline derivatives,trypsins, cimetidine, clarithromycin, clavulanic acid, clindamycin,clobutinol, clonidine, cotrimoxazole, codeine, caffeine, vitamin D andderivatives of vitamin D, colestyramine, cromoglicic acid, coumarin andcoumarin derivatives, cysteine, cytarabine, cyclophosphamide,ciclosporin, cyproterone, cytabarine, dapiprazole, desogestrel,desonide, dihydralazine, diltiazem, ergot alkaloids, dimenhydrinate,dimethyl sulphoxide, dimeticone, domperidone and domperidan derivatives,dopamine, doxazosin, doxorubizin, doxylamine, dapiprazole,benzodiazepines, diclofenac, glycoside antibiotics, desipramine,econazole, ACE inhibitors, enalapril, ephedrine, epinephrine, epoetinand epoetin derivatives, morphinans, calcium antagonists, irinotecan,modafinil, orlistat, peptide antibiotics, phenytoin, riluzoles,risedronate, sildenafil, topiramate, macrolide antibiotics, oestrogenand oestrogen derivatives, progestogen and progestogen derivatives,testosterone and testosterone derivatives, androgen and androgenderivatives, ethenzamide, etofenamate, etofibrate, fenofibrate,etofylline, etoposide, famciclovir, famotidine, felodipine, fenofibrate,fentanyl, fenticonazole, gyrase inhibitors, fluconazole, fludarabine,fluarizine, fluorouracil, fluoxetine, flurbiprofen, ibuprofen,flutamide, fluvastatin, follitropin, formoterol, fosfomicin, furosemide,fusidic acid, gallopamil, ganciclovir, gemfibrozil, gentamicin, ginkgo,Saint John's wort, glibenclamide, urea derivatives as oralantidiabetics, glucagon, glucosamine and glucosamine derivatives,glutathione, glycerol and glycerol derivatives, hypothalamus hormones,goserelin, gyrase inhibitors, guanethidine, halofantrine, haloperidol,heparin and heparin derivatives, hyaluronic acid, hydralazine,hydrochlorothiazide and hydrochlorothiazide derivatives, salicylates,hydroxyzine, idarubicin, ifosfamide, imipramine, indometacin,indoramine, insulin, interferons, iodine and iodine derivatives,isoconazole, isoprenaline, glucitol and glucitol derivatives,itraconazole, ketoconazole, ketoprofen, ketotifen, lacidipine,lansoprazole, levodopa, levomethadone, thyroid hormones, lipoic acid andlipoic acid derivatives, lisinopril, lisuride, lofepramine, lomustine,loperamide, loratadine, maprotiline, mebendazole, mebeverine, meclozine,mefenamic acid, mefloquine, meloxicam, mepindolol, meprobamate,meropenem, mesalazine, mesuximide, metamizole, metformin, methotrexate,methylphenidate, methylprednisolone, metixene, metoclopramide,metoprolol, metronidazole, mianserin, miconazole, minocycline,minoxidil, misoprostol, mitomycin, mizolastine, moexipril, morphine andmorphine derivatives, evening primrose, nalbuphine, naloxone, tilidine,naproxen, narcotine, natamycin, neostigmine, nicergoline, nicethamide,nifedipine, niflumic acid, nimodipine, nimorazole, nimustine,nisoldipine, adrenaline and adrenaline derivatives, norfloxacin,novamine sulfone, noscapine, nystatin, ofloxacin, olanzapine,olsalazine, omeprazole, omoconazole, ondansetron, oxaceprol, oxacillin,oxiconazole, oxymetazoline, pantoprazole, paracetamol, paroxetine,penciclovir, oral penicillins, pentazocine, pentifylline,pentoxifylline, perphenazine, pethidine, plant extracts, phenazone,pheniramine, barbituric acid derivatives, phenylbutazone, phenytoin,pimozide, pindolol, piperazine, piracetam, pirenzepine, piribedil,piroxicam, pramipexole, pravastatin, prazosin, procaine, promazine,propiverine, propranolol, propyphenazone, prostaglandins, protionamide,proxyphylline, quetiapine, quinapril, quinaprilat, ramipril, ranitidine,reproterol, reserpine, ribavirin, rifampicin, risperidone, ritonavir,ropinirole, roxatidine, roxithromycin, ruscogenin, rutoside and rutosidederivatives, sabadilla, salbutamol, salmeterol, scopolamine, selegiline,sertaconazole, sertindole, sertralion, silicates, sildenafil,simvastatin, sitosterol, sotalol, spaglumic acid, sparfloxacin,spectinomycin, spiramycin, spirapril, spironolactone, stavudine,streptomycin, sucralfate, sufentanil, sulbactam, sulphonamides,sulfasalazine, sulpiride, sultamicillin, sultiam, sumatriptan,suxamethonium chloride, tacrine, tacrolimus, taliolol, tamoxifen,taurolidine, tazarotene, temazepam, teniposide, tenoxicam, terazosin,terbinafine, terbutaline, terfenadine, terlipressin, tertatolol,tetracyclins, teryzoline, theobromine, theophylline, butizine,thiamazole, phenothiazines, thiotepa, tiagabine, tiapride, propionicacid derivatives, ticlopidine, timolol, tinidazole, tioconazole,tioguanine, tioxolone, tiropramide, tizanidine, tolazoline, tolbutamide,tolcapone, tolnaftate, tolperisone, topotecan, torasemide,antioestrogens, tramadol, tramazoline, trandolapril, tranylcypromine,trapidil, trazodone, triamcinolone and triamcinolone derivatives,triamterene, trifluperidol, trifluridine, trimethoprim, trimipramine,tripelennamine, triprolidine, trifosfamide, tromantadine, trometamol,tropalpin, troxerutine, tulobuterol, tyramine, tyrothricin, urapidil,ursodeoxycholic acid, chenodeoxycholic acid, valaciclovir, valproicacid, vancomycin, vecuronium chloride, Viagra, venlafaxine, verapamil,vidarabine, vigabatrin, viloazine, vinblastine, vinc amine, vincristine,vindesine, vinorelbine, vinpocetine, viquidil, warfarin, xantinolnicotinate, xipamide, zafirlukast, zalcitabine, zidovudine,zolmitriptan, zolpidem, zoplicone, zotipine and the like. In somenon-limiting examples, the pharmaceutical agent is rapamycin, arapamycin analogue such as for example, zatarolimus, tacrolimus, oreverolimus, estradiol, lantrunculin D, cytochalasin A, NO,dexamethasone, paclitaxel, and angiopeptin. See, e.g., U.S. Pat. No.6,897,205; see also U.S. Pat. Nos. 6,838,528; 6,497,729 Examples oftherapeutic agents employed in conjunction with the invention include,rapamycin, 40-O-(2-Hydroxyethyl)rapamycin (everolimus),40-O-Benzyl-rapamycin, 40-O-(4′-Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin40-O-(2-Hydroxy)ethoxycarbonylmethyl-rapamycin,40-O-(3-Hydroxyl)propyl-rapamycin 40-O-(6-Hydroxyl)hexyl-rapamycin40-O-[2-(2-Hydroxyl)ethoxy]ethyl-rapamycin40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,40-O-(2-Acetoxy)ethyl-rapamycin 40-O-(2-Nicotinoyloxy)ethyl-rapamycin,40-O-[2-(N -Morpholino)acetoxy]ethyl-rapamycin40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxyl)ethyl-rapamycin,28-O-Methyl-rapamycin, 40-O-(2-Aminoethyl)-rapamycin,40-O-(2-Acetaminoethyl)-rapamycin 40-O-(2-Nicotinamidoethyl) -rapamycin,40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin (tacrolimus),42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus), and 40-epi-(N1-tetrazolyl)-rapamycin (zotarolimus).

The active ingredients may, if desired, also be used in the form oftheir pharmaceutically acceptable salts or derivatives (meaning saltswhich retain the biological effectiveness and properties of thecompounds of this invention and which are not biologically or otherwiseundesirable), and in the case of chiral active ingredients it ispossible to employ both optically active isomers and racemates ormixtures of diastereoisomers.

“Stability” as used herein in refers to the stability of the drug in apolymer coating deposited on a substrate in its final product form(e.g., stability of the drug in a coated stent). The term stability willdefine 5% or less degradation of the drug in the final product form.

“Active biological agent” as used herein refers to a substance,originally produced by living organisms, that can be used to prevent ortreat a disease (meaning any treatment of a disease in a mammal,including preventing the disease, i.e. causing the clinical symptoms ofthe disease not to develop; inhibiting the disease, i.e. arresting thedevelopment of clinical symptoms; and/or relieving the disease, i.e.causing the regression of clinical symptoms). It is possible that theactive biological agents of the invention may also comprise two or moreactive biological agents or an active biological agent combined with apharmaceutical agent, a stabilizing agent or chemical or biologicalentity. Although the active biological agent may have been originallyproduced by living organisms, those of the present invention may alsohave been synthetically prepared, or by methods combining biologicalisolation and synthetic modification. By way of a non-limiting example,a nucleic acid could be isolated form from a biological source, orprepared by traditional techniques, known to those skilled in the art ofnucleic acid synthesis. Furthermore, the nucleic acid may be furthermodified to contain non-naturally occurring moieties. Non-limitingexamples of active biological agents include peptides, proteins,enzymes, glycoproteins, nucleic acids (including deoxyribonucleotide orribonucleotide polymers in either single or double stranded form, andunless otherwise limited, encompasses known analogues of naturalnucleotides that hybridize to nucleic acids in a manner similar tonaturally occurring nucleotides), antisense nucleic acids, fatty acids,antimicrobials, vitamins, hormones, steroids, lipids, polysaccharides,carbohydrates and the like. They further include, but are not limitedto, antirestenotic agents, antidiabetics, analgesics, antiinflammatoryagents, antirheumatics, antihypotensive agents, antihypertensive agents,psychoactive drugs, tranquillizers, antiemetics, muscle relaxants,glucocorticoids, agents for treating ulcerative colitis or Crohn'sdisease, antiallergics, antibiotics, antiepileptics, anticoagulants,antimycotics, antitussives, arteriosclerosis remedies, diuretics,proteins, peptides, enzymes, enzyme inhibitors, gout remedies, hormonesand inhibitors thereof, cardiac glycosides, immunotherapeutic agents andcytokines, laxatives, lipid-lowering agents, migraine remedies, mineralproducts, otologicals, anti parkinson agents, thyroid therapeuticagents, spasmolytics, platelet aggregation inhibitors, vitamins,cytostatics and metastasis inhibitors, phytopharmaceuticals andchemotherapeutic agents. Preferably, the active biological agent is apeptide, protein or enzyme, including derivatives and analogs of naturalpeptides, proteins and enzymes.

“Activity” as used herein refers to the ability of a pharmaceutical oractive biological agent to prevent or treat a disease (meaning anytreatment of a disease in a mammal, including preventing the disease,i.e. causing the clinical symptoms of the disease not to develop;inhibiting the disease, i.e. arresting the development of clinicalsymptoms; and/or relieving the disease, i.e. causing the regression ofclinical symptoms). Thus the activity of a pharmaceutical or activebiological agent should be of therapeutic or prophylactic value.

“Secondary, tertiary and quaternary structure” as used herein aredefined as follows. The active biological agents of the presentinvention will typically possess some degree of secondary, tertiaryand/or quaternary structure, upon which the activity of the agentdepends. As an illustrative, non-limiting example, proteins possesssecondary, tertiary and quaternary structure. Secondary structure refersto the spatial arrangement of amino acid residues that are near oneanother in the linear sequence. The α-helix and the β-strand areelements of secondary structure. Tertiary structure refers to thespatial arrangement of amino acid residues that are far apart in thelinear sequence and to the pattern of disulfide bonds. Proteinscontaining more than one polypeptide chain exhibit an additional levelof structural organization. Each polypeptide chain in such a protein iscalled a subunit. Quaternary structure refers to the spatial arrangementof subunits and the nature of their contacts. For example hemoglobinconsists of two α and two β chains. It is well known that proteinfunction arises from its conformation or three dimensional arrangementof atoms (a stretched out polypeptide chain is devoid of activity). Thusone aspect of the present invention is to manipulate active biologicalagents, while being careful to maintain their conformation, so as not tolose their therapeutic activity.

“Polymer” as used herein, refers to a series of repeating monomericunits that have been cross-linked or polymerized. Any suitable polymercan be used to carry out the present invention. It is possible that thepolymers of the invention may also comprise two, three, four or moredifferent polymers. In some embodiments, of the invention only onepolymer is used. In some preferred embodiments a combination of twopolymers are used. Combinations of polymers can be in varying ratios, toprovide coatings with differing properties. Those of skill in the art ofpolymer chemistry will be familiar with the different properties ofpolymeric compounds. Examples of polymers that may be used in thepresent invention include, but are not limited to polycarboxylic acids,cellulosic polymers, proteins, polypeptides, polyvinylpyrrolidone,maleic anhydride polymers, polyamides, polyvinyl alcohols, polyethyleneoxides, glycosaminoglycans, polysaccharides, polyesters, bacterialpolyesters (PHB, PHV), polyurethanes, polystyrenes, copolymers,silicones, polyorthoesters, polyanhydrides, copolymers of vinylmonomers, polycarbonates, polyethylenes, polypropylenes, polylacticacids, polyglycolic acids, polycaprolactones, polyhydroxybutyratevalerates, polyacrylamides, polyethers, polyurethane dispersions,polyacrylates, acrylic latex dispersions, polyacrylic acid, mixtures andcopolymers thereof. The polymers of the present invention may be naturalor synthetic in origin, including gelatin, chitosan, dextrin,cyclodextrin, Poly(urethanes), Poly(siloxanes) or silicones,Poly(acrylates) such as poly(methyl methacrylate), poly(butylmethacrylate), and Poly(2-hydroxy ethyl methacrylate), Poly(vinylalcohol) Poly(olefins) such as poly(ethylene), poly(isoprene),halogenated polymers such as Poly(tetrafluoroethylene)—and derivativesand copolymers such as those commonly sold as Teflon® products,Poly(vinylidine fluoride), Poly(vinyl acetate), Poly(vinyl pyrrolidone),Poly(acrylic acid), Polyacrylamide, Poly(ethylene-co-vinyl acetate),Poly(ethylene glycol), Poly(propylene glycol), Poly(methacrylic acid),Poly(dimethyl)-siloxane, Polyethylene terephthalate, Polyethylene-vinylacetate copolymer (PEVA), Ethylene vinyl alcohol (EVAL), Ethylene vinylacetate (EVA), Poly(styrene-b-isobutylene-b-styrene) (SIBBS),Phosophorycholine (PC), styrene-isobutylene, fluorinated polymers,polyxylenes (PARYLENE), tyrosine based polycarbonates, tyrosine basedpolyarylates, poly(trimethylene carbonate), hexafluoropropylene,vinylidene fluoride, butyl methacrylate, hexyl methacrylate, vinylpyrrolidinone, vinyl acetate, etc. Suitable polymers also includeabsorbable and/or resorbable polymers including the following,combinations, copolymers and derivatives of the following: Polylactides(PLA), Polyglycolides (PGA), Poly(lactide-co-glycolides) (PLGA),Polyanhydrides, Polyorthoesters, Poly(N-(2-hydroxypropyl)methacrylamide), Poly(1-aspartamide), Polyhydro-butyrate/-valeratecopolymer, Polyethyleneoxide/polybutylene terephthalate copolymer, etc.

“Therapeutically desirable morphology” as used herein refers to thegross form and structure of the pharmaceutical agent, once deposited onthe substrate, so as to provide for optimal conditions of ex vivostorage, in vivo preservation and/or in vivo release. Such optimalconditions may include, but are not limited to increased shelf life,increased in vivo stability, good biocompatibility, good bioavailabilityor modified release rates. Typically, for the present invention, thedesired morphology of a pharmaceutical agent would be crystalline orsemi-crystalline, although this may vary widely depending on manyfactors including, but not limited to, the nature of the pharmaceuticalagent, the disease to be treated/prevented, the intended storageconditions for the substrate prior to use or the location within thebody of any biomedical implant. Preferably at least 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90% or 100% of the pharmaceutical agent is incrystalline or semi-crystalline form.

“Stabilizing agent” as used herein refers to any substance thatmaintains or enhances the stability of the biological agent. Ideallythese stabilizing agents are classified as Generally Regarded As Safe(GRAS) materials by the US Food and Drug Administration (FDA). Examplesof stabilizing agents include, but are not limited to carrier proteins,such as albumin, gelatin, metals or inorganic salts. Pharmaceuticallyacceptable excipient that may be present can further be found in therelevant literature, for example in the Handbook of PharmaceuticalAdditives: An International Guide to More Than 6000 Products by TradeName, Chemical, Function, and Manufacturer; Michael and Irene Ash(Eds.); Gower Publishing Ltd.; Aldershot, Hampshire, England, 1995.

“Compressed fluid” as used herein refers to a fluid of appreciabledensity (e.g., >0.2 g/cc) that is a gas at standard temperature andpressure. “Supercritical fluid”, “near-critical fluid”,“near-supercritical fluid”, “critical fluid”, “densified fluid” or“densified gas” as used herein refers to a compressed fluid underconditions wherein the temperature is at least 80% of the criticaltemperature of the fluid and the pressure is at least 50% of thecritical pressure of the fluid.

Examples of substances that demonstrate supercritical or near criticalbehavior suitable for the present invention include, but are not limitedto carbon dioxide, isobutylene, ammonia, water, methanol, ethanol,ethane, propane, butane, pentane, dimethyl ether, xenon, sulfurhexafluoride, halogenated and partially halogenated materials such aschlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons,perfluorocarbons (such as perfluoromethane and perfluoropropane,chloroform, trichloro-fluoromethane, dichloro-difluoromethane,dichloro-tetrafluoroethane) and mixtures thereof.

“Sintering” as used herein refers to the process by which parts of thematrix or the entire polymer matrix becomes continuous (e.g., formationof a continuous polymer film). As discussed below, the sintering processis controlled to produce a fully conformal continuous matrix (completesintering) or to produce regions or domains of continuous coating whileproducing voids (discontinuities) in the matrix. As well, the sinteringprocess is controlled such that some phase separation is obtainedbetween polymer different polymers (e.g., polymers A and B) and/or toproduce phase separation between discrete polymer particles. Through thesintering process, the adhesions properties of the coating are improvedto reduce flaking of detachment of the coating from the substrate duringmanipulation in use. As described below, in some embodiments, thesintering process is controlled to provide incomplete sintering of thepolymer matrix. In embodiments involving incomplete sintering, a polymermatrix is formed with continuous domains, and voids, gaps, cavities,pores, channels or, interstices that provide space for sequestering atherapeutic agent which is released under controlled conditions.Depending on the nature of the polymer, the size of polymer particlesand/or other polymer properties, a compressed gas, a densified gas, anear critical fluid or a super-critical fluid may be employed. In oneexample, carbon dioxide is used to treat a substrate that has beencoated with a polymer and a drug, using dry powder and RESSelectrostatic coating processes. In another example, isobutylene isemployed in the sintering process. In other examples a mixture of carbondioxide and isobutylene is employed.

When an amorphous material is heated to a temperature above its glasstransition temperature, or when a crystalline material is heated to atemperature above a phase transition temperature, the moleculescomprising the material are more mobile, which in turn means that theyare more active and thus more prone to reactions such as oxidation.However, when an amorphous material is maintained at a temperature belowits glass transition temperature, its molecules are substantiallyimmobilized and thus less prone to reactions. Likewise, when acrystalline material is maintained at a temperature below its phasetransition temperature, its molecules are substantially immobilized andthus less prone to reactions. Accordingly, processing drug components atmild conditions, such as the deposition and sintering conditionsdescribed herein, minimizes cross-reactions and degradation of the drugcomponent. One type of reaction that is minimized by the processes ofthe invention relates to the ability to avoid conventional solventswhich in turn minimizes autoxidation of drug, whether in amorphous,semi-crystalline, or crystalline form, by reducing exposure thereof tofree radicals, residual solvents and autoxidation initiators.

“Rapid Expansion of Supercritical Solutions” or “RESS” as used hereininvolves the dissolution of a polymer into a compressed fluid, typicallya supercritical fluid, followed by rapid expansion into a chamber atlower pressure, typically near atmospheric conditions. The rapidexpansion of the supercritical fluid solution through a small opening,with its accompanying decrease in density, reduces the dissolutioncapacity of the fluid and results in the nucleation and growth ofpolymer particles. The atmosphere of the chamber is maintained in anelectrically neutral state by maintaining an isolating “cloud” of gas inthe chamber. Carbon dioxide or other appropriate gas is employed toprevent electrical charge is transferred from the substrate to thesurrounding environment.

“Bulk properties” properties of a coating including a pharmaceutical ora biological agent that can be enhanced through the methods of theinvention include for example: adhesion, smoothness, conformality,thickness, and compositional mixing.

“Solution Enhanced Dispersion of Supercritical Solutions” or “SEDS” asused herein involves a spray process for the generation of polymerparticles, which are formed when a compressed fluid (e.g. supercriticalfluid, preferably supercritical CO₂) is used as a diluent to a vehiclein which a polymer dissolved, (one that can dissolve both the polymerand the compressed gas). The mixing of the compressed fluid diluent withthe polymer-containing solution may be achieved by encounter of a firststream containing the polymer solution and a second stream containingthe diluent compressed fluid, for example, within one co-axial spraynozzle or by the use of multiple spray nozzles or by the use of multiplefluid streams co-entering into a mixing zone. The solvent in the polymersolution may be one compound or a mixture of two or more ingredients andmay be or comprise an alcohol (including diols, triols, etc.), ether,amine, ketone, carbonate, or alkanes, or hydrocarbon (aliphatic oraromatic) or may be a mixture of compounds, such as mixtures of alkanes,or mixtures of one or more alkanes in combination with additionalcompounds such as one or more alcohols. (e.g., from 0 or 0.1 to 5% of aC₁ to C₁₅ alcohol, including diols, triols, etc.). See for example U.S.Pat. No. 6,669,785. The solvent may optionally contain a surfactant, asalso described in (for example) U.S. Pat. No. 6,669,785.

In one embodiment of the SEDS process, a first stream of fluidcomprising a polymer dissolved in a common solvent is co-sprayed with asecond stream of compressed fluid. Polymer particles are produced as thesecond stream acts as a diluent that weakens the solvent in the polymersolution of the first stream. The now combined streams of fluid, alongwith the polymer particles, flow into a collection vessel. In anotherembodiment of the SEDS process, a first stream of fluid comprising adrug dissolved in a common solvent is co-sprayed with a second stream ofcompressed fluid. Drug particles are produced as the second stream actsas a diluent that weakens the solvent in the drug solution of the firststream. The now combined streams of fluid, along with the drugparticles, flow out into a collection vessel. Control of particle size,particle size distribution, and morphology is achieved by tailoring thefollowing process variables: temperature, pressure, solvent compositionof the first stream, flow-rate of the first stream, flow-rate of thesecond stream, composition of the second stream (where soluble additivesmay be added to the compressed gas), and conditions of the capturevessel. Typically the capture vessel contains a fluid phase that is atleast five to ten times (5-10×) atmospheric pressure.

“Electrostatically charged” or “electrical potential” or “electrostaticcapture” as used herein refers to the collection of the spray-producedparticles upon a substrate that has a different electrostatic potentialthan the sprayed particles. Thus, the substrate is at an attractiveelectronic potential with respect to the particles exiting, whichresults in the capture of the particles upon the substrate. i.e. thesubstrate and particles are oppositely charged, and the particlestransport through the fluid medium of the capture vessel onto thesurface of the substrate is enhanced via electrostatic attraction. Thismay be achieved by charging the particles and grounding the substrate orconversely charging the substrate and grounding the particles, or bysome other process, which would be easily envisaged by one of skill inthe art of electrostatic capture.

“Open vessel” as used herein refers to a vessel open to the outsideatmosphere, and thus at substantially the same temperature and pressureas the outside atmosphere.

“Closed vessel” as used herein refers to a vessel sealed from theoutside atmosphere, and thus may be at significantly differenttemperatures and pressures to the outside atmosphere.

EXAMPLES

The following examples are given to enable those skilled in the art tomore clearly understand and to practice the present invention. Theyshould not be considered as limiting the scope of the invention, butmerely as being illustrative and representative thereof.

Example 1 Dry Powder Rapamycin Coating on an Electrically Charged 316Stainless Steel Coupon

A 1 cm×2 cm stainless steel metal coupon serving as a target substratefor rapamycin coating was placed in a vessel and attached to a highvoltage electrode. The vessel (V), of approximately 1500 cm³ volume, wasequipped with two separate nozzles through which rapamycin or polymerscould be selectively introduced into the vessel. Both nozzles weregrounded. Additionally, the vessel (V) was equipped with a separate portwas available for purging the vessel. Upstream of one nozzle (D) was asmall pressure vessel (PV) approximately 5 cm³ in volume with threeports to be used as inlets and outlets. Each port was equipped with avalve which could be actuated opened or closed. One port, port (1) usedas an inlet, was an addition port for the dry powdered rapamycin. Port(2), also an inlet was used to feed pressurized gas, liquid, orsupercritical fluid into PV. Port (3), used as an outlet, was used toconnect the pressure vessel (PV) with nozzle (D) contained in theprimary vessel (V) with the target coupon. Dry powdered rapamycinobtained from LC Laboratories in a predominantly crystalline solidstate, 50 mg milled to an average particle size of approximately 3microns, was loaded into (PV) through port (1) then port (1) wasactuated to the closed position. Gaseous carbon dioxide was then addedto (PV) to a pressure of 400 to 600 psig at 20° C. through port (2),then port (2) was closed to the source gas. The metal coupon was thencharged to 40 kV using a Glassman Series EL high-voltage power source.Port (3) was then actuated open allowing for the expansion of thepressurized carbon dioxide and rapamycin powder into the vessel (V)while the coupon remained charged. After approximately 60-seconds thevoltage was eliminated and the coupon was isolated. Upon visualinspection of the coupon using an optical microscope it was determinedthat the entire surface area of the coupon, other than a small portionmasked by the voltage lead, was covered in a relatively evendistribution of powdered material. X-ray diffraction (XRD) confirmedthat the powdered material was largely crystalline in nature asdeposited on the metal coupon. UV-Vis and FTIR spectroscopy confirmedthat the material deposited on the coupon was rapamycin.

Example 2 Dry Powder Rapamycin Coating on a 316-Stainless Steel Couponwith No Electrical Charge

A coupon was coated in an identical fashion to what was described inExample 1. However, no voltage was applied to the coupon throughout thedry powder-coating run. After expansion of the carbon dioxide and thepowdered rapamycin into vessel (V), and a period of roughly 60 seconds,the coupon was isolated and evaluated. The coupon was analyzed using anoptical microscope and showed some dry powder material on much of thesurface of the coupon. However, the coverage of drug on the surface wasmuch lower than in example 1 and there was notably more variability incoverage at different locations on the coupon surface. The total powdercoating was estimated to be about ⅓rd the amount determined to becrystalline rapamycin in example 1.

Example 3 Polymer Coating on an Electrically Charged 316-Stainless SteelCoupon Using Rapid Expansion from a Liquefied Gas

A coating apparatus as described in example 1 above was used in theforegoing example. In this example the second nozzle, nozzle (P), wasused to feed precipitated polymer particles into vessel (V) to coat a316-stainless steel coupon. Nozzle (P) was equipped with a heater andcontroller to minimize heat loss due to the expansion of liquefiedgases. Upstream of nozzle (P) was a pressure vessel, (PV2), withapproximately 25-cm3 internal volume. The pressure vessel (PV2) wasequipped with multiple ports to be used for inlets, outlets,thermocouples, and pressure transducers. Additionally, (PV2) wasequipped with a heater and a temperature controller. Each port wasconnected to the appropriate valves, metering valves, pressureregulators, or plugs to ensure adequate control of material into and outof the pressure vessel (PV2). One outlet from (PV2) was connected to ametering valve through pressure rated tubing which was then connected tonozzle (P) located in vessel (V). In the experiment, 75 mg ofpolyethylene-co-vinyl acetate (PEVA) obtained from Aldrich ChemicalCompany with approximately 33-weight percent vinyl acetate and 75 mg ofpoly(butyl methacrylate) (PBMA) also obtained from Aldrich ChemicalCompany were added to pressure vessel (PV2). Dichlorofluoromethane, 20.0grams, was added to the pressure vessel (PV2) through a valve and inlet.Pressure vessel (PV2) was then heated to 40° C. bringing the pressureinside the isolated vessel to approximately 40 psig. Nozzle (P) washeated to 120° C. After sufficient time to dissolve the two polymers inthe liquefied gas inside (PV2), the vessel (PV2) was over-pressurizedwith helium to approximately 200 psig using a source helium tank and adual stage pressure regulator. See U.S. Pat. No. 6,905,555 for adescription of Helium displacement art. A 1-cm×2-cm 316-stainless steelcoupon was placed into vessel (V) and attached to an electrical lead.Nozzle (P) was attached to ground. The coupon was charged to 40 kV usinga Glassman high-voltage power source at which point the metering valvewas opened between (PV2) and nozzle (P) in pressure vessel (PV). Polymerdissolved in liquefied gas and over-pressurized with helium to 200 psigwas fed at a constant pressure of 200 psig into vessel (V) maintained atatmospheric pressure through nozzle (P) at an approximate rate of 3.0cm³/min. After approximately 5 seconds, the metering valve was closeddiscontinuing the polymer-solvent feed. Vessel (V) was purged withgaseous CO₂ for 30 seconds to displace chlorofluorocarbon. Afterapproximately 30 seconds, the metering valve was again opened for aperiod of approximately 5 seconds and then closed. This cycle wasrepeated about 4 times. After an additional 1-minute the applied voltageto the coupon was discontinued and the coupon was removed from pressurevessel (V). Upon inspection by optical microscope, a polymer coating wasevident as evenly distributed on all non-masked surfaces of the coupon.Dissolution of the polymer mixture from the surface of the couponfollowed by quantification using standardized quantitative FT-IR methodsdetermined a composition of approximately 1:1 PEVA to PBMA on thecoupon.

Example 4 Dual Coating of a Metal Coupon with Crystalline Rapamycin, and1:1 Mixture of Polyethylene-Co-Vinyl Acetate (PEVA) and Poly(ButylMethacrylate) (PBMA)

An apparatus described in example ‘1’ and further described in example‘3’ was used in the foregoing example. In preparation for the coatingexperiment, 25 mg of crystalline powdered rapamycin with an averageparticle size of 3-microns was added to (PV) through port (1), then port(1) was closed. Then, (PV) was pressurized to 400-600 psig with gaseouscarbon dioxide at 20° C. through port (2), prior to closing port (2).Next, 75 mg of polyethylene-co-vinyl acetate (PEVA) with approximately33-weight percent vinyl acetate and 75 mg of poly(butyl methacrylate)(PBMA) were added to pressure vessel (PV2). Dichlorofluoromethane, 20.0grams, was added to the pressure vessel (PV2) through a valve and inlet.Pressure vessel (PV2) was then heated to 40° C. bringing the pressureinside the isolated vessel (PV2) to approximately 40 psig. Nozzle (P)was heated to 120° C. After sufficient time to dissolve the two polymersin the liquefied gas, the vessel was over-pressurized with helium toapproximately 200 psig using a source helium tank and a dual stagepressure regulator. A 1-cm×2-cm 316-stainless steel coupon was added tovessel (V) and connected to a high-voltage power lead. Both nozzles (D)and (P) were grounded. To begin, the coupon was charged to 40 kV afterwhich port (3) connecting (PV) containing rapamycin to nozzle (D) wasopened allowing expansion of carbon dioxide and ejection of rapamycininto vessel (V) maintained at ambient pressure. After closing port (3)and approximately 60-seconds, the metering valve connecting (PV2) withnozzle (P) inside vessel (V) was opened allowing for expansion ofliquefied gas to a gas phase and introduction of precipitated polymerparticles into vessel (V) while maintaining vessel (V) at ambientpressure. After approximately 5-seconds at a feed rate of approximately3 cm³/min., the metering valve was closed while the coupon remainedcharged. Port (1) was then opened and an additional 25-mg of powderedcrystalline rapamycin was added to (PV), and then port (1) was closed.Pressure vessel (PV) was then pressurized with liquid carbon dioxide to400-600 psig through port (2), after which port (2) was again closed.Maintaining the coupon at an applied voltage of 40 kV, port (3) wasagain opened to nozzle (D) allowing for the expansion of carbon dioxideto a gas and the ejection of the powdered crystalline drug into thevessel (V). After and additional 60-seconds, the metering valve between(PV2) and nozzle (P) was again opened allowing for the expansion of theliquefied solvent to a gas into vessel (V) and the precipitation ofpolymer particles also in vessel (V). The sequential addition of drugfollowed by polymer or polymer followed by drug as described above wasrepeated for a total of four (4) cycles after which the appliedpotential was removed from the coupon and the coupon was removed fromthe vessel. The coupon was then examined using an optical microscope. Aconsistent coating was visible on all surfaces of the coupon exceptwhere the coupon was masked by the electrical lead. The coating appearedconformal but opaque and somewhat granular at high magnification.

Example 5 Dual Coating of a Metal Coupon with Crystalline Rapamycin, and1:1 Mixture of Polyethylene-Co-Vinyl Acetate (PEVA) and Poly(ButylMethacrylate) (PBMA) Followed by Supercritical Carbon Dioxide Annealingor Gaseous Carbon Dioxide Annealing

After inspection of the coupon created in example 4, the coated couponwas carefully placed in a pressure vessel that was pressurized withcarbon dioxide to a pressure of 4500 psig and at a temperature of 60° C.This CO₂ sintering process was done to enhance the physical propertiesof the film on the coupon. The coupon remained in the vessel under theseconditions for approximately 3 hours after which the supercritical CO₂was slowly vented from the pressure vessel and then the coupon wasremoved and reexamined under an optical microscope. The coating wasobserved to be conformal, consistent, and semi-transparent as opposed tothe opaque coating observed and reported in example 4 without densecarbon dioxide treatment. The coated coupon was then submitted for x-raydiffraction (XRD) analysis to confirm the presence of crystallinerapamycin in the polymer matrix. XRD confirmed the presence ofcrystalline rapamycin.

Example 6 Dual Coating of a Metal Cardiovascular Stent with CrystallineRapamycin, and 1:1 Mixture of Polyethylene-Co-Vinyl Acetate (PEVA) andPoly(Butyl Methacrylate) (PBMA)

The apparatus described in examples 1, 3, and 4 above was used in theforegoing example. The metal stent used was a Tristar™ Coronary Stent ofa nominal size of 3 mm by 13 mm. The stent was coated in an identicalfashion to the coupon described in example 4 above. The stent was coatedin an alternating fashion whereby the first coating layer of drug wasfollowed by a thin layer of polymer. These two steps, called adrug/polymer cycle, were repeated 3-times so that the last appliedcoating layer was polymer. After completion of the coating step, thestent was removed from the vessel (V) and placed in a small pressurevessel where it was exposed to supercritical CO₂ as described above inexample 4. After this low temperature annealing step, the stent wasremoved and examined using an optical microscope. The stent was thenanalyzed using a scanning electron microscope (SEM) equipped with a fastion bombarding (FIB) device to provide cross-sectional analysis of thecoated stent. The SEM micrograph at multiple locations on the stentindicated a completely conformal coating of between 6 and 15-microns inthickness. Evidence of rapamycin crystallites was also apparent in themicrographs.

Example 7 Layered Coating of a Cardiovascular Stent with anAnti-Restenosis Therapeutic and Polymer in Layers to Control DrugElution Characteristics

A cardiovascular stent is coated using the methods described in examples‘5’ and ‘6’ above. The stent is coated in such as way that the drug andpolymer are in alternating layers. The first application to the barestent is a thin layer of a non-resorbing polymer, approximately2-microns thick. The second layer is a therapeutic agent withanti-restenosis indication. Approximately 35 micrograms are added inthis second layer. A third layer of polymer is added at approximately2-microns thick, followed by a fourth drug layer which is composed ofabout 25 micrograms of the anti-restenosis agent. A fifth polymer layer,approximately 1-micron thick is added to stent, followed by the sixthlayer that includes the therapeutic agent of approximately15-micrograms. Finally, a last polymer layer is added to a thickness ofabout 2-microns. After the coating procedure, the stent is annealedusing carbon dioxide as described in example 4 above. In this example adrug eluting stent (DES) is described with low initial drug “burst”properties by virtue of a “sequestered drug layering” process, notpossible in conventional solvent-based coating processes. Additionally,by virtue of a higher concentration of drug at the stent ‘inter-layer’the elution profile is expected to reach as sustained therapeuticrelease over a longer period of time.

Example 8 Layered Coating of a Cardiovascular Stent with anAnti-Restenosis Therapeutic and an Anti-Thrombotic Therapeutic in aPolymer Matrix

A cardiovascular stent is coated as described in example 7 above. Inthis example, after a first polymer layer of approximately 2-micronsthick, a drug with anti-thrombotic indication is added in a layer ofless than 2-microns in thickness. A third layer consisting of thenon-resorbing polymer is added to a thickness of about 4-microns. Nextanother drug layer is added, a different therapeutic, with ananti-restenosis indication. This layer contains approximately 100micrograms of the anti-restenosis agent. Finally, a polymer layerapproximately 2-microns in thickness is added to the stent. Aftercoating the stent is treated as described in example 4 to anneal thecoating using carbon dioxide.

Example 9 Coating of Stents with Rapamycin, Polyethylene-Co-VinylAcetate (PEVA) and Polybutyl Methacrylate (PBMA)

Micronized Rapamycin was purchased from LC Laboratories. PBMA (Mw=˜237k) and PEVA (33% vinyl acetate content) were purchased from AldrichChemicals. Two kinds of stents were used: 3 mm TriStar® from Guidant and6 cell×8-mm, BX Velocity® from Cordis. The stents were coated by dryelectrostatic capture followed by supercritical fluid sintering, using 3stents/coating run and 3 runs/data set. The coating apparatus isrepresented in FIG. 2. Analysis of the coated stents was performed bymultiple techniques on both stents and coupons with relevant controlexperiments.

In this example a 1:1 ratio of PEVA and PBMA is dissolved in aDichlorofluoromethane (CCl₂FH), which is a compressed gas solvent knownto be in the class of “Freon” chemicals. The physical properties of thisparticular Freon are as follows:

-   BP=8.9 C-   Tc=178.33 C-   Pc=751.47 psig-   Dc=0.526014 g/cc

A solution was formed by mixing 30 mg of the combined polymers per gramdichlorofluoromethane. The solution was then maintained at 60° C. atvapor pressure (approx 28 psig) until the solution was ready to spray.The solution was then pressurized by adding an immiscible gas to the topof the vessel—typically Helium. Adding Helium compressed theFreon+polymer solution up to 700 (+/−50 psig), which resulted in acompressed fluid. The polymer+Freon solution was then pushed through anozzle having an inner diameter of 0.005″ by continuous addition ofHelium into the vessel. The solvent (dichlorofluoromethane) is rapidlyvaporized coming out of the nozzle (which is heated to 120 C), as it'sboiling point is significantly below room temperature.

The Drug is deposited by dry powder spray coating. Between 10-30 mg ofdrug are charged into a small volume of tubing, which is thenpressurized with gaseous CO₂ to 400 psig. The mixture flows through anozzle having an inner diameter of 0.187″ into the coating vessel wherethe stents are held. During electrostatic deposition, the stent ischarged and the nozzles are grounded. FIGS. 1 and 2 show the apparatusused for the coating and sintering process.

Example 10 Optical Microscopy Analysis of Rapamycin/PEVA/PBM CoatedStents

The stents produced in example 9 were examined by optical microscopy, at40× magnification with back and side lighting. This method was used toprovide a coarse qualitative representation of coating uniformity and togenerally demonstrate the utility of the low-temperature CO₂ annealingstep. The resulting photos shown in FIG. 3, demonstrate the differencesin appearance (a) before and (b) after annealing in dense carbon dioxideat 40° C. Photos of the outside, edge and inside surfaces are presentedin FIG. 4 (a), prior to sintering, which clearly shows nanoparticledeposition equally on all surfaces of the stent, and 4(b) aftersintering, with the film showing a smooth and optically transparentpolymer. FIG. 5 shows additional 40× magnified images ofRapamycin/PEVA/PBMA coated stents, showing the outside and insidesurfaces, (a) before sintering, further demonstrating the nanoparticledeposition equally on all surfaces of the stent and (b) after sintering,showing a smooth and optically transparent polymer film. FIG. 6 shows a100× magnified mages of Rapamycin/PEVA/PBMA Coated Stents. Crystallinedrug is clearly visible embedded within a highly uniform polymercoating.

Example 11 Scanning Electron Microscopy Analysis of Rapamycin/PEVA/PBMCoated Stents

The stents produced in example 9 were examined by scanning electronmicroscopy, and the resulting images presented in FIGS. 7 at (a) ×30magnification, (b) ×250 magnification, (c) ×1000 magnification and (d)×3000 magnification. Clearly the nanoparticles have been sintered to aneven and conformal film, with a surface topology of less than 5 microns,and demonstrate clear evidence of embedded crystalline rapamycin.

Cross-sectional (FIB) images were also acquired and are shown in FIG.8(a) at 7000× and (b) 20000× magnification. An even coating ofconsistent thickness is visible. Four cross-sectional thicknesses weremeasured: (1) 10.355 μM, (2) 10.412 μM, (3) 10.043 μM and (4) 10.157 μM,to give an average thickness of 10.242 μM, with only 2% (±0.2 μM)variation.

Example 12 Differential Scanning Calorimetry (DSC) of Rapamycin/PEVA/PBMCoated Stents

The stents produced in example 9 were examined by Differential Scanningcalorimetry (DSC). Control analyses s of PEVA only, PBMA only andRapamycin only are shown in FIGS. 9 (a), (b) and (c) respectively. TheDSC of the Rapamycin, PEVA and PBMA coated stent is shown in FIG. 9 (d).The rapamycin crystalline melt is clearly visible at 185-200° C. anddistinct from those of the polymers.

Example 13 X-Ray Diffraction (XRD) of Rapamycin/PEVA/PBM Coated Stents

The stents produced in example 9 were examined by X-Ray Diffraction(XRD). The control spectrum of micro-ionized Rapamycin powder is shownin FIG. 10 (a). The XRD of the Rapamycin, PEVA and PBMA coated, sinteredstent is shown in FIG. 10 (b), showing that the Rapamycin remainscrystalline (˜64%) throughout the coating and sintering process.

Example 14 Confocal Raman Analysis of Rapamycin/PEVA/PBM Coated Stents

The stents produced in example 9 were examined by Confocal RamanAnalysis, to provide depth profiling from the coating surface down tothe metal stent. FIG. 11 (a) shows the Rapamycin depth profile outsidecircumference (Rapamycin peak at ˜1620) and 11 (b) shows the polymerdepth profile outside circumference, clearly demonstrating that the drugis distributed throughout polymer coated stents. The highest drugcontent appears in the center of the polymer coating (˜4 μM from the airsurface), which is controllable, via the coating and sinteringconditions used. In certain embodiments of the invention, the drug wouldbe close to the air surface of the coating. In other embodiments, thedrug would be closer to the metal stent. In other embodiments, more thanone drug would be deposited in the coating, wherein one drug would becloser to the air surface and another drug would be closer to the metalsurface. In yet other embodiments, the drugs would be distributedtogether throughout the coating.

Example 15 UV-Vis and FT-IR Analysis of Rapamycin/PEVA/PBM Coated Stentsfor Quantification of Coating Components

A UV-VIS method was developed and used to quantitatively determine themass of rapamycin coated onto the stents with poly(ethylene-co-vinylacetate) (PEVA) and poly(butyl methacrylate) (PBMA). The UV-Vis spectrumof Rapamycin is shown in FIG. 12 (a) and a Rapamycin calibration curvewas obtained, λ@277 nm in ethanol, as shown in FIG. 12 (b). Rapamycinwas dissolved from the coated stent in ethanol, and the drugconcentration and mass calculated. An average mass of 74±11 μg Rapamycinwas loaded onto the stents. The results in FIG. 13 (a) show a consistentdrug coating: (+/−) 15% stent-to-stent, (+/−) 12% run-to-run, (meanconcentrations (3 stents each); 4 cell by 8 mm parylene coated).

An FT-IR method was developed and used to quantitatively determine themass of PEVA and PBMA coated onto stents with rapamycin. The FT-IRspectra of PEVA and PBMA is shown in FIG. 12 (c) and calibration curveswere obtained using Beer's Law for PEVA λ@˜1050 cm⁻¹ and PBMA λ@˜1285cm⁻¹, as shown in FIGS. 12(d) and (e), respectively. The polymers weredissolved from the coated stent in methylene chloride, and the polymerconcentrations and the masses calculated accordingly. An average mass of1060±190 μg PEVA and 1110±198 μg PBMA was loaded onto the stents. Theresults in FIGS. 13 (b) and (c) show a consistent polymer coating: (+/−)18% stent-to-stent, (+/−) 15% run-to-run, (mean concentrations (3 stentseach); 4 cell by 8 mm parylene coated).

Example 16 Coating of Stents with Paclitaxel/PEVA/PMBA

3 mm Guidant TriStar® Stents were coated with a Paclitaxel/PEVA/PMBAcomposite, by processes of the invention, as described herein. Thecoated stents were examined by optical microscopy, and photos of theoutside surface of the stent (a) prior to sintering and (b) aftersintering are shown in FIG. 14. FIG. 15 (a) represents the UV-Viscalibration curve developed for Paclitaxel, λ@228 nm in ethanol, usingthe methods of example 15, as described above. Rapamycin was dissolvedfrom the coated stent in ethanol, and the drug concentration and masscalculated, to give an average mass of 148±14 μg loaded Rapamycin, asshown in FIG. 15 (b).

Example 17 UV-Vis and FT-IR Analysis of Rapamycin/PEVA/PBM Coated Stentsfor Quantification of Coating Components

The UV-VIS and FT-IR methods, described in example 15, were used todetermine the quantities of Rapamycin, PEVA and PBMA respectively, fromstents coated with Rapamycin, PEVA and PBMA by processes of theinvention, as described herein. The component quantifications are shownin FIG. 16 and calculated; (a) an average mass of 81±3 μg Rapamycin wasloaded onto the stents, (b) an average mass of 391±69 μg PEVA and (c)268±64 μg PBMA was loaded onto the stents.

Example 18 Coating of Stents with Rapamycin or Paclitaxel,Polyethylene-Co-Vinyl Acetate (PEVA) and Polybutyl Methacrylate (PBMA)

A 25 mL stainless steel reservoir is charged with 150.0±0.1 mg ofpoly(ethylene co-vinyl acetate) (PEVA) and 150.0±0.1 mg of poly(butylmethacrylate) (PBMA) to which is transferred 20.0±0.3 grams ofdichlorofluoromethane. The pressure rises in the reservoir toapproximately 28 psig. The reservoir is heated to 60° C. aftertransferring dichlorofluoromethane to the reservoir. The reservoir isthen pressurized with helium until the pressure reaches 700±30 psig.Helium acts as a piston to push out the dichlorofluoromethane-polymersolution. The reservoir is isolated from the system by appropriatevalving. A second stainless steel reservoir with volume of 15±1 mL ischarged with 13 mg of drug compound (rapamycin or Paclitaxel). Thisreservoir is pressurized to 400±5 psig with carbon dioxide gas. Thetemperature of the drug reservoir is room temperature. The reservoir isisolated from the system by appropriate valving. A third reservoir ischarged with tetrahydrofuran or dichloromethane solvent so that thepolymer nozzle can be flushed between polymer sprays. This reservoir isalso pressurized with helium to 700 psig and isolated from the system byappropriate valving. The polymer spray nozzle is heated to 120±2° C.while the drug spray nozzle remains at room temperature. Stents areloaded into the stent fixture and attached to a high voltage source viaan alligator clamp. The alligator clamp enters the coating chamber viaan electrically insulated pass through. Carbon dioxide gas is admittedinto the coating vessel at 8 psig for a period of 5 minutes through athird gas flush nozzle to remove air and moisture to eliminate arcingbetween the nozzles and components held at high potential. Afterflushing the coating chamber with carbon dioxide gas, a potential of 35kV is applied to the stents via a high voltage generator. This potentialis maintained during each coating step of polymer and drug. Thepotential is removed when the polymer spray nozzle is flushed withtetrahydrofuran or dichloromethane. Polymer solution is sprayed for 7secs from the polymer solution reservoir into the coating chamber. Theapplied potential is turned off and the polymer nozzle is removed fromthe coating chamber and flushed with solvent for 2 minutes and thenflushed with helium gas for approximately one minute until all solventis removed from the nozzle. The coating chamber is flushed with carbondioxide gas during the nozzle solvent flush to flush outdichlorofluoromethane gas. The polymer spray nozzle is placed back inthe coating chamber and the carbon dioxide gas flush is stopped. A 35 kVpotential is applied to the stents and the drug compound is rapidlysprayed into the coating chamber by opening appropriate valving. Afterone minute of rest time, polymer spray commences for another sevenseconds. The process can be repeated with any number of cycles.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

The various analytical methods developed to examine the coated stentsand the results they generated are summarized in the table below:

Analytical Method To Provide Result Optical microscope Visible images ofthe stents. Nanoparticles deposited evenly on Empirical survey ofcoating uniformity all surfaces of stent Sintering to conformal film(with visual evidence of crystalline drug) SEM Top-down andcross-sectional images Very smooth and conformal films (electronmicrographs) at various at high magnification magnifications. 10.2 ± 0.3μm well-sintered films Gross estimates of coating uniformity and viacross-sectional analysis thickness X-ray diffraction Quantitativeindication of drug +65% crystalline rapamycin on (XRD) morphology incoated films on proxy proxy samples substrates Differential Qualitativeevidence of crystalline Demonstrated rapamycin Scanning rapamycin fromproxy substrates crystalline melt (185-200° C.) Calorimetry (DSC)(crystalline melt) Confocal Raman Compositional data (drug, polymer A,Drug distributed throughout Polymer B) at various depths in the film onpolymer coated stents the coated stents (i.e. surface, 2 μm deep, 4- μmdeep, etc.) UV-Vis Quantitative compositional information for 74 ± 11 μgdrug loaded onto stents, Spectroscopy drug loading on ‘sacrificial’coated stents, run-to-run control within 12% BL method deviation FT-IRQuantitative compositional information for 1060 ± 190 μg PEVA loadedonto spectroscopy loading of both polymers on ‘sacrificial’ stentscoated stents, BL method 1110 ± 198 μg PBMA loaded onto stents

Example 19 Preparation of Supercritical Solution Comprising,Polyethylene-Co-Vinyl Acetate (PEVA) and Polybutyl Methacrylate (PBMA)in Isobutylene

75 mg of PEVA and 75 mg of PBMA are placed in a 25 mL view cell. Theview cell is heated to 150° C.

Isobutylene is added to a pressure of 3000 psig. Under these conditions,a clear solution is produced.

Example 20 Preparation of Supercritical Solution ComprisingPolyethylene-Co-Vinyl Acetate (PEVA) and Polybutyl Methacrylate (PBMA)in Isobutylene

150 mg of PEVA and 150 mg of PBMA are placed in a 25 mL view cell. Theview cell is heated to 150° C.

Isobutylene is added to a pressure of 4000 psig. Under these conditions,a clear solution is produced.

Example 21 Preparation of Supercritical Solution ComprisingPolyethylene-Co-Vinyl Acetate (PEVA) and Polybutyl Methacrylate (PBMA)in Isobutylene and CO₂

75 mg of PEVA and 75 mg of PBMA are placed in a 25 mL view cell and thecell is heated to 150° C.

Isobutylene is added to a pressure of 4000 psig, to produce a clearsolution.

10 (v/v %) CO₂ is added. The addition of CO₂ at this volume percent doesnot precipitate the dissolved polymer.

Example 22 Preparation of Supercritical Solution ComprisingPolyethylene-Co-Vinyl Acetate (PEVA) and Polybutyl Methacrylate (PBMA)in Isobutylene and CO₂

150 mg of PEVA and 150 mg of PBMA are placed in a 25 mL view cell andthe cell is heated to 150° C.

Isobutylene is added to a pressure of 4000 psig, to produce a clearsolution.

10 (v/v %) CO₂ is added. The addition of CO₂ at this volume percent doesnot precipitate the dissolved polymer; however addition of CO₂ at highervolume fraction leads to polymer precipitation, under these conditions.

Example 23

This example illustrates how the present invention provides a method foroptimal design of therapeutic profiles using both anti-restenosis andanti-thrombotic compounds to address both short and long-term safety ofdrug-eluting stents. This approach which includes multi-drugformulations in biodegradable polymers has the potential to provideimproved benefits for both patients and clinicians. The exampleillustrates an embodiment of the invention to deliver drug-elutingstents by maintaining morphology of therapeutic compounds and providingmanufacturing processes that apply discrete and independent therapieswithin a single, multi-therapy coating under these conditions.

As discussed above, many processes for spray coating stents require thatdrug and polymer be dissolved in solvent or mutual solvent before spraycoating can occur. The present invention provides a method to spray coatstents with drug(s) and polymer(s) in independent steps under conditionsthat do not require dissolved drug and separates drug and polymerspraying into individual steps. This capability allows discreteplacement of drug within a polymer matrix and makes possible placingmore than one drug on a single medical device with or without anintervening polymer layer. Discrete deposition and elution of a dualdrug coated drug eluting stent using the present invention is summarizedbelow.

Methods: Taxol (98% purity) was purchased from Toronto ResearchChemicals. Heparin was purchased from Polysciences, Inc.Polyethylene-co-vinyl acetate (33% w/w vinyl acetate) andPolybutylmethacrylate were purchased from Sigma-Aldrich and used withoutfurther purification. All solvents unless otherwise noted were suppliedby Sigma-Aldrich and were spectrophotometric grade and used withoutfurther purification. Three stents manufactured to requestedspecifications (Burpee Materials Technology, L.L.C.) were coatedsimultaneously. Polymer was applied to stents using an electrostaticrapid expansion of a supercritical solution method (RESS) as describedabove while Heparin and Taxol were applied to stents using a dry powdercoating method also described above. Heparin was deposited prior todepositing Taxol with an intervening polymer layer. Heparin was analyzedby UV-Vis spectrophotometry (Ocean Optics) and quantified using theBeer-Lambert relationship using an Azure A assay while Taxol wasdetermined directly from the elution medium at 227 nm. Coated stentswere removed from the coating chamber and sintered at 30° C. andapproximately 4 bar using the sintering method described above. Taxoldrug elution from the polymer matrix was completed by eluting stents inphosphate buffered saline at pH 7.4 with added tween 20 (0.05% w/w) in athermostatically controlled temperature bath held at 37° C. An aqueousmedia was used to elute heparin from the polymer matrix. Because ofsurfactant interference with the azure A assay, heparin elution wasquantitatively determined separately from Taxol.

Results: Heparin was loaded on the stent at 70 micrograms and Taxol wasloaded on the stent at 78 micrograms. The total polymer mass depositedon the stent was 2.1 milligrams. Heparin and Taxol elution was monitoredfor 15 days. FIG. 24 shows the cumulative mass of heparin eluted as wellas the elution rate. The ability of azure A to continue to bind toheparin suggests that no chemical reaction between heparin and Taxoloccurs.

In summary, in certain embodiments, the present invention provides amethod for coating drug-eluting stents. Polymer(s) and drug(s) areapplied in a controlled, low-temperature, solvent-free process. In oneembodiment Rapamycin, PBMA and PEVA are applied to provide a conformal,consistent coating at target Rapamycin loading, in a 1:1 mixture ofPBMA:PEVA, at a thickness of ˜10 μM, containing zero residual solvent.The Rapamycin is deposited in crystalline morphology (+50%). TheRapamycin/PEVA/PBMA film is applied using a dry process, wherein thedrug and polymer content is highly controllable, and easily adaptablefor different drugs, different (resorbable and permanent) polymers,multiple drugs on a single stent, and provides for a high degree ofstent-to-stent precision. The absence of traditional solvents duringdeposition enables control over drug content at variable film depths.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A method of depositing a coating on a substratecomprising: a. providing a substrate; b. depositing at least one polymerlayer in dry powder form onto said substrate; c. depositing at least onepharmaceutical layer comprising a first pharmaceutical agent in drypowder form onto said substrate without use of a solvent; and d.sintering said at least one polymer layer so as to produce a polymerfilm fused and adhered to said substrate under conditions that do notsubstantially modify a morphology of said first pharmaceutical agent,wherein said first pharmaceutical agent comprises a morphology that iscrystalline or semi-crystalline.
 2. The method of claim 1, wherein saidat least one of said polymer layer comprises a bioabsorbable polymer. 3.The method of claim 1 wherein said polymer of said at least one polymerlayer is selected from PLA, PLGA, PGA and Poly(dioxanone).
 4. The methodof claim 1 comprising depositing 5 or more layers as follows: a firstpolymer layer the first layer comprising said first pharmaceutical agenta second polymer layer the second layer comprising a secondpharmaceutical agent; and a third polymer layer.
 5. The method of claim1 comprising depositing 4 or more layers as follows: a first polymerlayer the first layer comprising said first pharmaceutical agent asecond polymer layer; and the second layer comprising a secondpharmaceutical agent.
 6. The method of claim 1 comprising depositing 4or more layers as follows: the first layer comprising said firstpharmaceutical agent a first polymer layer the second layer comprising asecond pharmaceutical agent; and a second polymer layer.
 7. The methodof claim 1 comprising depositing 3 or more layers as follows: the firstlayer comprising said first pharmaceutical agent a polymer layer; and asecond layer comprising a second pharmaceutical agent.
 8. The method ofclaim 1 wherein said first layer and said at least one polymer layercomprising alternate layers of pharmaceutical agent, or pharmaceuticalagent and polymer, and layers of polymer without pharmaceutical agent.9. The method of claim 8, wherein the pharmaceutical agent layers aresubstantially free of polymer and the polymer layers are substantiallyfree of pharmaceutical agent.
 10. The method of claim 1 comprisingdepositing 5, 10, 20, 50, or 100 layers.
 11. The method of claim 4wherein said first pharmaceutical agent has an elution profile that isslower than the elution profile of said second pharmaceutical agent. 12.The method of claim 11 wherein the second pharmaceutical agent achieves100% elution in about 5 days to about 20 days and the firstpharmaceutical agent achieves 100% elution in about 120 days to about180 days.
 13. The method of claim 4, wherein said first pharmaceuticalagent is anti-thrombogenic agent and said second pharmaceutical agent isan anti-restenotic agent.
 14. The method of claim 4, wherein said firstpharmaceutical agent is heparin and said second pharmaceutical agent istaxol or a macrolide immunosuppressive (limus) drug.
 15. The method ofclaim 2, wherein said bioabsorbable polymer is selected from PGApoly(glycolide), LPLA poly(l-lactide), DLPLA poly(dl-lactide), PCLpoly(e-caprolactone) PDO, poly(dioxolane) PGA-TMC, 85/15 DLPLGp(dl-lactide-co-glycolide), 75/25 DLPLG, 65/35 DLPLG, 50/50 DLPLG, TMCpoly(trimethylcarbonate), and p(CPP:SA) poly(1,3-bis-p-(carboxyphenoxy)propane-co-sebacic acid).
 16. The method of claim 1,wherein said pharmaceutical agent comprises a macrolideimmunosuppressive (limus) drug.
 17. The method of claim 16, wherein themacrolide immunosuppressive drug comprises one or more of rapamycin,40-O-(2-Hydroxyethyl)rapamycin (everolimus), 40-O-Benzyl-rapamycin, 40-O-(4′Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin, 40-O-(2Hydroxy)ethoxycarbonylmethyl-rapamycin, 40-O-(3-Hydroxy)propyl-rapamycin, 40-O-(6-Hydroxy)hexyl-rapamycin, 40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin,40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,40-O-(2-Acetoxy)ethyl-rapamycin, 40-O-(2-Nicotinoyloxy)ethyl -rapamycin,40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin,40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O -ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxy)ethyl -rapamycin,28-O-Methyl-rapamycin, 40-O-(2-Aminoethyl)-rapamycin,40-O-(2-Acetaminoethyl)-rapamycin, 40-O-(2-Nicotinamidoethyl)-rapamycin, 40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin, 40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl) rapamycin (tacrolimus),42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus), and 40-epi-(N1-tetrazolyl)-rapamycin (zotarolimus). 18.The method of claim 16, wherein said macrolide immunosuppressive drug isat least 50% crystalline.
 19. The method of claim 1, wherein saiddepositing of said at least one polymer layer comprises depositingpolymer particles on said substrate by an RESS process.
 20. The methodof claim 1, wherein the substrate is a biomedical implant selected fromthe group consisting of a stent, electrode, catheter, lead, implantablepacemaker or cardioverter housing, joint, screw, rod, ophthalmicimplant, prosthetic, and shunt.
 21. A multi drug coated substratecomprising a. a substrate; and b. at least one polymer layer; c. apharmaceutical layer comprising at least one pharmaceutical agent;wherein said at least one polymer layer comprises a sintered layer inwhich the morphology of said pharmaceutical agent in said coating hasnot been substantially modified and said first pharmaceutical agent iscrystalline or semi-crystalline, and wherein the coated substrate issubstantially free of residual solvent.
 22. The substrate of claim 21,wherein said at least one polymer layer comprises a bioabsorbablepolymer.
 23. The substrate of claim 21 wherein said polymer of said atleast one polymer layer is selected from PLA, PLGA, PGA andPoly(dioxanone).
 24. The substrate of claim 21 comprising 5 or morelayers as follows: a first polymer layer a first pharmaceutical layercomprising said at least one pharmaceutical agent a second polymer layera second pharmaceutical layer comprising a second pharmaceutical agent;and a third polymer layer.
 25. The substrate of claim 21 comprising 4 ormore layers as follows: a first polymer layer a first pharmaceuticallayer comprising said at least one pharmaceutical agent a second polymerlayer; and a second pharmaceutical layer comprising a secondpharmaceutical agent.
 26. The substrate of claim 21 comprising 4 or morelayers as follows: the first pharmaceutical layer comprising a firstpharmaceutical agent a first polymer layer a second pharmaceutical layercomprising a second pharmaceutical agent; and a second polymer layer.27. The substrate of claim 21 comprising 3 or more layers as follows: afirst pharmaceutical layer comprising said first pharmaceutical agent apolymer layer; and a second pharmaceutical layer comprising a secondpharmaceutical agent.
 28. The substrate of claim 21 wherein saidpharmaceutical layer and said at least one polymer layer comprisesalternate layers of pharmaceutical agent, or pharmaceutical agent andpolymer, and layers of polymer without pharmaceutical agent.
 29. Thesubstrate of claim 27, wherein pharmaceutical is substantially free ofpolymer and said at least one polymer layer is substantially free ofpharmaceutical agent.
 30. The substrate of claim 21 comprisingdepositing 5, 10, 20, 50, or 100 layers.
 31. The substrate of claim 24wherein said first pharmaceutical layer has an elution profile that isslower than the elution profile of said second pharmaceutical agent. 32.The substrate of claim 31 wherein the second pharmaceutical agentachieves 100% elution in about 5 days to about 20 days and the firstpharmaceutical agent achieves 100% elution in about 120 days to about180 days.
 33. The substrate of claim 24, wherein said firstpharmaceutical agent is anti-thrombogenic agent and said secondpharmaceutical agent is an anti-restenotic agent.
 34. The substrate ofclaim 24, wherein said first pharmaceutical agent is heparin and saidsecond agent is taxol or a macrolide immunosuppressive (limus) drug. 35.The substrate of claim 22, wherein said bioabsorbable polymer isselected from PGA poly(glycolide), LPLA poly(l-lactide), DLPLApoly(dl-lactide), PCL poly(e-caprolactone) PDO, poly(dioxolane) PGA-TMC,85/15 DLPLG p(dl-lactide-co -glycolide), 75/25 DLPLG, 65/35 DLPLG, 50/50DLPLG, TMC poly(trimethylcarbonate), and p(CPP:SA) poly(1,3-bis-p-(carboxyphenoxy)propane-co-sebacic acid).
 36. The substrate of claim24, wherein at least one of said pharmaceutical agents comprise amacrolide immunosuppressive (limus) drug.
 37. The substrate of claim 36,wherein the macrolide immunosuppressive drug comprises one or more ofrapamycin, 40-O-(2-Hydroxyethyl)rapamycin (everolimus), 40-O-Benzyl-rapamycin, 40-O-(4′-Hydroxymethyl)benzyl-rapamycin, 40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl) -rapamycin,40-O-(2-Hydroxy)ethoxycarbonylmethyl-rapamycin,40-O-(3-Hydroxy)propyl-rapamycin, 40-O-(6-Hydroxy)hexyl-rapamycin,40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin,40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,40-O-(2-Acetoxy)ethyl-rapamycin, 40-O-(2-Nicotinoyloxy)ethyl-rapamycin,40-O-[2-(N-Morpholino)acetoxy]ethyl -rapamycin,40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin, 40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl-rapamycin,40-O-(2-Aminoethyl)-rapamycin, 40-O-(2-Acetaminoethyl)-rapamycin,40-O-(2-Nicotinamidoethyl)-rapamycin,40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi -(tetrazolyl)rapamycin (tacrolimus),42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus), and 40-epi-(N1-tetrazolyl)-rapamycin (zotarolimus). 38.The substrate of claim 36, wherein the macrolide immunosuppressive drugis at least 50% crystalline.
 39. The substrate of claim 21, wherein thesubstrate is a biomedical implant selected from the group consisting ofa stent, electrode, catheter, lead, implantable pacemaker orcardioverter housing, joint, screw, rod, ophthalmic implant, prosthetic,and shunt.
 40. The method of claim 1 wherein said depositing of said atleast one polymer layer and said depositing of said at least onepharmaceutical layer are carried out simultaneously.
 41. The method ofclaim 1 wherein said depositing of said at least one polymer layer andsaid depositing of said at least one pharmaceutical layer are carriedout in succession.